Hepatocellular carcinoma in Korea: introduction and overview]

Hepatocellular carcinoma (HCC) is a highly malignant, generally fatal neoplasm arising from hepatocytes. HCC accounts for over 80% of all primary liver cancers which ranks fourth among the organ-specific causes of cancer-related deaths worldwide. HCC is particularly prevalent in Korea where the age standardized incidence rate is 46.5 per 100,000 population. Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or presence of liver cirrhosis are important risk factors for HCC development globally. Infection with HBV is the most important risk for HCC in Asia except Japan. The high incidence rate of HCC in Korea is thought to be related to the high carrier rate (5-6%) of HBV, which is currently being fought via a nationwide vaccination program. Although progress has been made in the management of HCC including chemoembolization and local ablation therapy, there has been little overall reduction in HCC mortality during the past 20 years. Recently, five year survival rate of primary liver cancer is 9.6% in Korea. Such poor prognosis of HCC results from the late detection of cancer, an aggressive tumor biology and underlying chronic liver diseases. Only a limited proportion of patients are candidates for potentially curative forms of treatment. Therefore efforts should be directed toward an effective surveillance program. The early detection of HCC is the important approach in reducing HCC mortality in the short term. Because almost eighty percent of HCC is diagnosed in late stage, we launched a nationwide surveillance program to screen high risk groups (HBV or HCV carriers or liver cirrhosis, over 40 years old) and formulated the Korean practice guideline for the diagnosis and treatment of HCC with special emphasis on advanced stage of HCC.     

Modalities of prevention of recurrence after tumor ablation/resection of HCC

Abstract   Hepatocellular carcinoma (HCC) is now the third cause of death in Japan. For the last 20-30 years, there has been an exponential increase of HCC and now reaching 34,000 death a year. Approximately 80% of those are due to hepatitis C virus (HCV) infection, and 10–20% due to hepatitis B virus (HBV). Thus, we need to find a better way of prevention from infection to development of HCC. By understanding the 'natural' course of the infection, we may find the strategies to prevent HCC (primary prevention), and also to prevent the recurrence in patients who already developed HCC (secondary prevention). This will drastically reduce the incidence of HCC, and prolong the patients' life.     

Epidemiology of hepatocellular carcinoma in Japan

Primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), has ranked third in men and fifth in women as a cause of death from malignant neoplasm in Japan. Although the number of deaths and death rates from HCC increased until 2002 in Japan, annual deaths (34 089) and the death rate (27.0/100 000) from liver cancer decreased in 2003. Hepatitis C virus (HCV)-related HCC represents 75% of all HCC in Japan. The incidence of HCC without hepatitis B surface antigen (HBsAg) or anti-HCV accounted for 7–12% of HCC in Japan andhalf of non-B non-C-HCC was of unknown origin. Geographically, HCC is more frequent in western than eastern Japan, and the death rates from HCC in each prefecture correlate with the prevalence of anti-HCV, but not with HBsAg prevalence. Interferon therapy for chronic hepatitis C has reduced the risk factors for development of HCC, especially among patients with sustained response.     

Current status and clinical course of hepatitis C virus in Korea

The mortality due to chronic liver disease, including liver cirrhosis and hepatocellular carcinoma (HCC), ranks as one of the highest in Korea. The prevalence rates of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections in the general Korean population are approximately 1 and 5%, respectively. Blood transfusion was the strongest risk factor for the transmission of HCV infection. Therefore, the evaluation of risk factors for HCV infection including blood transfusion, intravenous drug user, hemophilia, and hemodialysis, is important. The most prevalent HCV genotype is 1b followed by 2a. The annual incidence of HCC among HCV-related liver cirrhosis has been estimated at 5%, and approximately 12% of HCC is attributable to HCV and 68% to HBV in Korea. HCV infection is more closely associated with HCC in elderly patients than HBV-related HCC. Even though the prevalence of anti-HCV in Korea has been reduced and the risk of HCV transmission through blood transfusion has markedly decreased, public-health programs to prevent de novo infections should be developed. This review describes the HCV prevalence and risk factors among the general population, and the distribution of HCV genotypes as well as the clinical course of HCV in Korea.     

Antiviral therapy and primary and secondary prevention of hepatocellular carcinoma

Viral hepatitis due to chronic hepatitis B and C virus (HBV/HCV) infects more than 500 000 000 individuals worldwide. These chronic viral diseases are highly linked to the development of hepatocellular carcinoma (HCC), the fifth most common cause of cancer death worldwide. HCC is much more common in Asia and Africa than in the USA and Europe, although HCC is one of the few cancers with a rising incidence in the USA. There are 530 000 cases of HCC worldwide of which 82% are related to viral hepatitis. 316 000 cases of HCC are HBV-associated, 118 000 are HCV-associated. The most effective way to prevent HCC is to prevent viral infection through immunization. Currently there are effective vaccinesagainst hepatitis B and A, but not against HCV, the virus that accounts for most HCC in the USA. The published work supporting the use of antiviral therapy in preventing liver cancer is limited. Data supporting the use of antiviral therapy in preventing recurrence of HCC after initial anticancer approaches is even less available. Nevertheless, the weight of evidence suggests that treatment of HBV/HCV-related fibrosis will reduce the risk of developing HCC.     

Estimates and projections of hepatitis B-related hepatocellular carcinoma in Australia among people born in Asia-Pacific countries

Background and Aim:  Australia has increasing immigration from hepatitis B virus (HBV) endemic countries of the Asia-Pacific region (APR). This study estimates immigration-related chronic HBV cases, chronic HBV prevalence, and HBV-related hepatocellular carcinoma (HCC) from 1960 to 2005 and projects HBV-related HCC to 2025 in Australia among people born in the APR.
Methods:  The populations of APR origin for the period 1960–2005 were derived from Australian census data. HBV prevalence from population-based serosurveys in the APR countries was used to estimate new chronic HBV cases (immigrant arrivals per year with chronic HBV). Age-specific incidence rates of HCC derived from a Taiwanese population-based study were used to estimate and project HBV-related HCC.
Results:  Chronic HBV cases among APR-born population increased rapidly from the late 1970s reaching a peak of 4182 in 1990. Chronic HBV prevalence increased to >53 000 in 2005. Estimates of HBV-related HCC increased linearly from one in 1960 to 140 in 2005, with a projected increase to 250 in 2025. Universal HBV vaccination programs in countries of origin had limited impact on projected HBV-related HCC to 2025.
Conclusion:  The burden of chronic HBV including HBV-related HCC among APR-born Australians has increased over the past three decades and is projected to increase further during the next two decades.     

Application of surveillance programs for hepatocellular carcinoma in the Asia–Pacific Region

Hepatocellular carcinoma (HCC) is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations and curative therapy is possible only for small tumors. Surveillance has been recommended by regional liver societies and is practiced widely, but its benefits are not clearly established. Hepatic ultrasonography with or without alpha fetoprotein (AFP) performed every 6 months is the preferred program. Surveillance of HCC has been well shown to detect small tumors for curative treatment, which may be translated to improved patient survival. However, most studies are limited by lead-time bias, length bias for early diagnosis of small HCC, different tumor growth rates and poor compliance with surveillance. Cost-effectiveness of surveillance programs depends on the rate of small HCC detected 'accidentally' (routine imaging) in a comparator group, annual incidence of HCC with various etiologies, patient age and the availability of liver transplantation. The incremental cost-effectiveness for 6-monthly AFP and ultrasound has been estimated from approximately $US26 000–74 000/quality adjusted life years (QALY). All cirrhotic patients are therefore recommended for HCC surveillance unless the disease is too advanced for any curative treatment. As chronic hepatitis B can develop into HCC without going through liver cirrhosis, high-risk non-cirrhotic chronic hepatitis B patients are also recommended for HCC surveillance. In conclusion, HCC surveillance could be effective at reducing disease-specific mortality with acceptable cost-effectiveness among selected patient groups, provided it is a well-organized program.     

Hepatocellular carcinoma

Male sex, age, cirrhosis, and HBsAg are the major risk factors for hepatocellular carcinoma (HCC). The geographic distribution of HCC is highly uneven, such that three distinct incidence areas are recognized. To clarify the reason(s) for this geographic variability of HCC, the risk factors in each incidence area were assessed. In parallel with the geographic distribution of HCC, HBsAg prevalence was highest in both HCC patients and in general population in Africa and Asia, where mothers of HCC patients are frequently HBsAg-positive, suggesting that hepatitis B virus hyperendemicity and perinatal infection account for the high HCC incidence in these areas. Cirrhosis, which is found on autopsy in 80% of the cases of HCC patients worldwide, is the most prevalent risk factor for HCC in areas where hepatitis B virus infection is less common. However, HBsAg carriage adds to the HCC risk carried by cirrhosis and explains the higher incidence of HCC in cirrhotics from Africa and Asia as well as elsewhere. Available data suggest that chronic HCV infection is a risk factor for cirrhosis and HCC. HBV vaccination should decrease HCC incidence rates worldwide; however, HCC prevention in regions where HBsAg carriage is infrequent may also require prevention of the other causes of cirrhosis in order for HCC rates to decline.     

Risk Factors for the Development of Hepatocellular Carcinoma in Thailand

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The incidence of HCC is on the rise in Thailand, where it has become the most common malignancy in males and the third most common in females. Here, we review some of the risk factors that have contributed to this increase in HCC incidence in the Thai population. Hepatitis B virus (HBV) is the main etiologic risk factor for HCC, followed by hepatitis C virus (HCV). Patients with HBV genotype C have a higher positive rate of hepatitis B early antigen (HBeAg) and progress to cirrhosis and HCC earlier than genotype B. For HCV patients, 16% developed HCC associated cirrhosis by year 5 after diagnosis, and the cumulative risk for death from HCC at year 10 was 60%. Dietary exposure to the fungal hepatocarcinogen aflatoxin B1 has been shown to interact synergistically with HBV infection to increase the risk of early onset HCC. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. In recent years, obesity and metabolic syndrome have markedly increased the incidence of HCC and are important causes of HCC in some resource-rich regions.     

Geographic characterization of hepatitis virus infections,genotyping of hepatitis B virus,and p53 mutation in hepatocellular carcinoma analyzed by in situ detection of viral genomes from carcinoma tissues: comparison among six different countries

We investigated the relationship of infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) to p53 mutation in hepatocellular carcinomas (HCC) from six countries, including Japan, China, Korea, Vietnam, Spain, and the Unites States. For this purpose, we used formalin-fixed, paraffin-embedded liver tissues obtained from 449 patients with HCC to detect the viral and p53 genes by polymerase chain reaction (PCR). HBV was the most prevalent in Korea (69.1%), China (66.1%), Vietnam (60.5%), and Spain (38.6%). In contrast, HCV was the most prevalent in Japan (59.8%) and in the United States (41.5%). Type C of HBV was the most common genotype (78.6%) encountered in HCC in these countries. Importantly, among 125 intrahepatic HBV DNA-positive patients, 44 (35.2%) were serologically negative for HBsAg (occult hepatitis B). Based on PCR, immunohistochemical, serological, and clinical findings, 4.8% of HCC patients were diagnosed with non-B, non-C. A point mutation at exon 7 of p53 was detected in 20 of the 239 HCC samples examined, including those from 9 Chinese, 5 American, 2 Japanese, 2 Korean, and 2 Spanish patients, respectively. Interestingly, a point mutation with an amino acid substitution at codon 251 (Ile-->Asn) was detected frequently in 11 of 20 (55%) cases. A specific mutation induced by Aflatoxin B1 at codon 249 was seen in two patients, both Chinese. Our results suggest that genotype C of HBV may play an important role in hepatocarcinogenesis in different geographic regions, and that in situ detection of HBV genomes could be important for clarifying the agent(s) of unknown etiology related to HCC.     

Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus

Aim:  Patients with high serum hepatitis B virus (HBV) DNA concentrations are at high risk of tumor recurrence after liver resection for HBV-related hepatocellular carcinoma (HCC).
Methods:  Among 24 patients with high serum HBV DNA concentrations who underwent liver resection for HBV-related HCC, postoperative lamivudine therapy was chosen by 14 (lamivudine group). The other 10 patients were controls.
Results:  Clinicopathologic findings did not differ between the groups. Tumor-free survival rate after surgery was significantly higher in the lamivudine than the control group ( P  = 0.0086). By univariate analysis, multiple tumors were also a risk factor for a short tumor-free survival. By multivariate analysis, lack of lamivudine therapy and multiple tumors were independent risk factors for a short tumor-free survival. In four patients YMDD mutant viruses were detected after beginning lamivudine administration; in two of them, adefovir dipivoxil was administered because of sustained serum alanine aminotransferase elevations.
Conclusion:  Lamivudine therapy improved tumor-free survival rate after curative resection of HBV-related HCC in patients with high serum concentrations of HBV DNA, although careful follow up proved necessary for the detection of YMDD mutant viruses.     

Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in Japan

In the 2008 guidelines for the treatment of patients with cirrhosis, who are infected with hepatitis B virus (HBV), the main goal is to normalize levels of alanine and aspartate aminotransferases by eliminating HBV or reducing viral loads. In patients with compensated cirrhosis, the clearance of HBV from serum is aimed for by entecavir, as the main resort, for histological improvement toward the prevention of hepatocellular carcinoma (HCC). In patients with decompensated cirrhosis, by contrast, meticulous therapeutic strategies are adopted for the reversal to compensation, toward the eventual goal of decreasing the risk of HCC. For maintaining liver function and preventing HCC, branched chain amino acids and nutrient supplements are applied, in addition to conventional liver supportive therapies. For patients with chronic hepatitis B, separate guidelines are applied to those younger than 35 years and those aged 35 years or older. Even for patients with chronic hepatitis who are negative for hepatitis e antigen (HBeAg), but who harbor HBV DNA in titers of 7 log copies/mL or more, a "drug-free state" is aimed for by sequential treatment with interferon (IFN) plus entecavir as the first line. For patients with chronic hepatitis B aged 35 years or older, who are HBeAg-negative and carry HBV DNA in titers of less than 7 log copies/mL, long-term IFN for 24–48 weeks is adopted anew. To HBeAg-negative patients who have either or both platelet counts of less than 150 × 10³/mm³ and less than 7 log copies of HBV DNA, also, long-term IFN for 24–48 weeks is indicated.     

Hepatocellular carcinoma in the Asia pacific region

Primary liver cancer, particularly hepatocellular carcinoma (HCC) remains a significant disease worldwide. It is among the top three causes of cancer death in the Asia Pacific region because of the high prevalence of its main etiological agents, chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. In this region, the incidence of HCC has been static over recent decades. Older age is a major risk factor; the incidence increasing sharply after age 40 years. There is a male predilection, with male to female ratio of 3:1, except in elderly Japanese with equal sex incidence or female predominance. In most Asia‐Pacific countries, chronic HBV infection accounts for 75–80% of cases; Japan, Singapore and Australia/New Zealand are exceptions because of higher prevalence of HCV infection. In spite of advances in surgery, liver transplantation and newer pharmaco/biological therapies, the survival rate has improved only slightly over recent decades, and this could be attributable to earlier diagnosis (‘lead‐time bias’). The majority of patients present with advanced diseases, hence reducing the chance of curative treatment. The importance of HCC may decrease in two to three decades when the prevalence of chronic HBV infection decreases as a result of the universal HBV vaccination programs implemented in late 1980s in most Asia‐Pacific countries, and because of reduced incidence of medical transmission of HCV. However, transmission of HCV by injection drug use, and rising prevalence of obesity and diabetes, both independent risk factors for HCC, may partly offset this decline.     

Characteristics and prognosis of patients in Japan with viral marker-negative hepatocellular carcinoma

Background and Aim: The characteristics and prognosis of patients with hepatitis virus marker‐negative hepatocellular carcinoma (HCC) is not fully elucidated in Japan. We investigated the characteristics and prognosis of HCC patients in whom no markers for hepatitis virus infection were detected, in comparison with those of HCC patients with hepatitis virus infection. Methods: Viral markers for hepatitis B and C virus (HBV and HCV) infection were measured in 1152 patients in whom initial HCC was diagnosed between 1991 and 2004. Patient characteristics, characteristics of HCC and survival were compared between patients in whom no marker was positive (viral marker‐negative HCC) and those in whom chronic HBV or HCV infection was confirmed by viral markers (viral HCC). Results: Overall, 119 patients (10.3%) were shown to have viral marker‐negative HCC. Hepatocellular carcinoma was detected under surveillance in a significantly smaller percentage of patients with viral marker‐negative HCC than of patients with viral HCC (P < 0.0001). The tumor was significantly larger (P < 0.0001) and vascular invasion was significantly more prevalent (P = 0.0003) in patients with viral marker‐negative HCC than in those with viral HCC. The survival rate of patients with viral marker‐negative HCC was significantly lower than that of patients with viral HCC (P = 0.0378). Conclusion: The patients with HCC in whom hepatitis viral infection had not been confirmed tended not to be under surveillance, resulting in the detection of HCC at more advanced stage and with a poorer prognosis. Efforts to identify patients without hepatitis virus infection who should be under surveillance for HCC will be necessary in the future.     

HBV genotypes in India: do they influence disease severity?

Aims:  Association of HBV genotypes (especially A and D) with severity of liver disease is controversial. We studied the influence of HBV genotypes on liver disease severity among Indian patients.
Methods:  We selected 247 HBV infected patients (42 acute hepatitis, 87 carriers, 44 chronic hepatitis B [CHB], 35 liver cirrhosis [LC] and 40 hepatocellular carcinoma [HCC]). Genotyping of stored sera was performed using genotype-specific enzyme-linked immunosorbent assay (ELISA) and restriction fragment length polymorphism (RFLP). The distribution of genotypes in disease states of differing clinical, histological and biochemical severity were compared.
Results:  The most common genotype was D (162/237, 68.3%), followed by A (61, 25.7%) and C (14, 5.9%). The distribution of HBV genotypes between patients with acute hepatitis and CHB (carriers + CHB + LC + HCC), or between carriers and disease states (CHB + LC + HCC), or between mild chronic infection (carriers + CHB) and complications of chronic HBV infection (LC + HCC) was similar. Eighty-seven patients had liver biopsy; the median histological activity index (HAI) and fibrosis stage at baseline were similar between genotype groups (four [1–9] genotype A [ n  = 28]), three (2–4) genotype C ( n  = 4) and four (1–10) genotype D ( n  = 55); P  = 0.33 for HAI score; (0.5 [0–6] genotype A, 0.5 [0–4] genotype C and 1 [0–6] genotype D; P  = 0.92 for fibrosis stage). The response to therapy was similar between the genotypes.
Conclusion:  Clinical, histological severity and therapeutic responses are similar among patients with HBV genotypes A and D.     

Hepatocellular carcinoma and other primary liver cancers in hepatitis C patients in Sweden - a low endemic country

Summary.  The aim of this study was to assess the risk of hepatocellular carcinoma (HCC) and other primary liver cancers (PLC) in the nationwide cohort of hepatitis C virus (HCV) infected patients in Sweden. The basis was the total HCV-cohort notified in 1990–2004, after excluding 3238 people also reported with hepatitis B, the study cohort consisted of 36 126 people contributing an observation time of 246 105 person-years. The most common route of transmission was intravenous drug use (57%). The national Cancer Registry was used for follow-up, and 354 developed PLC (mainly HCC), of whom 234 were eligible for statistical analysis. The PLC incidence in the HCV cohort was compared with the incidence in the general population, and a standardized incidence ratio (SIR) was calculated for six different strata according to estimated duration of infection. The highest relative risk, SIR: 46 (95% CI: 36–56) was found in the stratum 25–30 years with HCV infection and SIR: 40 (95% CI: 31–51) in the stratum 30–35 years with infection. In the entire community-based HCV cohort in Sweden we found a highly increased risk of liver cancer compared to the general population. The highest relative risk was among people who had been infected for more than 25 years.     

Prevention of hepatocellular carcinoma]

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and has the third highest mortality rate among malignancies in South Korea. Despite the continuing efforts for the early detection of HCC, the mortality rate and prognosis have not been improved yet. Its clinical behavior is quite different from other cancers. High recurrence rate after curative treatment might be the reason for poor prognosis. Several methods including chemoprevention, blocking the development of HCC, have been under investigations. The vaccine for hepatitis, in the form of primary prevention, is considered to be the most effective one inhibiting the development of liver disease. Furthermore, keeping away from hepatotoxic agents is another way for preventing liver cell injuries. Secondary prevention is to stop the development of HCC in chronic liver diseases. Since the level of DNA in hepatitis B virus (HBV) hepatitis patients is closely related with the development of HCC, it is helpful to lower the DNA level using anti-viral agents. In addition, IFN, one of the anti-viral agents, can inhibit HCV hepatitis from tumorigenesis. Cyclo-oxygenase (COX)-2 inhibitors are also alleged to have a function in interrupting the development of HCC. Tertiary prevention means the prevention of recurrence of HCC after successful treatment. Because of high recurrence rate, the prevention of recurrence should be one of the important factors affecting the prognosis of HCC. Up to now, COX inhibitors, retinoic acids, vitamin K2, glycyrrhizin epigallocatechin-3-gallate (EGCG), and ginseng had been reported to be effective for the chemoprevention of HCC. Further studies are required for an advancement in the prevention of HCC.     

Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma

Chronic hepatitis B virus(HBV) infection is a critical risk factor for the carcinogenesis and progression of hepatocellular carcinoma(HCC). It promotes HCC development by inducing liver fibrogenesis, genetic and epigenetic alterations, and the expression of active viral-coded proteins. Effective antiviral treatments inhibit the replication of HBV, reduce serum viral load and accelerate hepatitis B e antigen serum conversion. Timely initiation of antiviral treatment is not only essential for preventing the incidence of HCC in chronic hepatitis B patients, but also important for reducing HBV reactivation, improving liver function, reducing or delaying HCC recurrence, and prolonging overall survival of HBV-related HCC patients after curative and palliative therapies. The selection of antiviral drugs, monitoring of indicators such as HBV DNA and hepatitis B surface antigen, and timely rescue treatment when necessary, are essential in antiviral therapies for HBVrelated HCC.     

GB virus C/hepatitis G virus infection among patients with hepatocellular carcinoma in the inshore area of the Yangtze river, China

To investigate the association between GB virus C/hepatitis G virus (GBV-C/HGV) infection and the development of hepatocellular carcinoma (HCC) in H city, in the inshore area of the Yangtze River, where high prevalence of HCC has been reported, we determined hepatitis B virus (HBV) and hepatitis C virus (HCV) markers, GBV-C/HGV-RNA and GBV-C/HGV E₂ antibody (anti-HG E₂) among 114 HCC patients and the same number of age- and sex-matched controls. There were no significant differences in the clinical and demographic characteristics between them, except for serum alanine aminotransferase level and history of liver diseases. There was a significant difference of hepatitis B virus surface antigen (HBsAg) prevalence between the HCC patients (75.4%) and the controls (20.2%; P < 0.01). Hepatitis C virus antibody was detected in 4.4% of the HCC patients, compared with 1.7% of the controls. GB virus-C/HGV-RNA and anti-HG E₂ were detected in 14.9 and 1.7% of the HCC patients, respectively, compared with 7.0 and 1.7% of the controls, respectively. Nucleotide sequences and molecular evolutionary analysis showed the strains of GBV-C/HGV-RNA were classified into genotype 2 and 3 (HG and ASIA type). An effect analysis showed an odds ratio (OR) for developing HCC from GBV-C/HGV infection among HBsAg-positive subjects was 14.9, with a 95% CI of 4.9–45.4. HBsAg infection alone was 13.83 (95% CI 7.4–25.9) and GBV-C/HGV infection alone, 3.74 (95% CI 1.1–13.1), respectively. These data indicate that HBV infection is considered to be one of the major risk factors in patients with HCC and although GBV-C/HGV infection was observed in both the HCC and the control groups, it might not play an important role in the development of HCC in this area.